Osteoporosis is one of the most important disorders of our aging population. Many epidemiologic studies provide evidence for a strong genetic component to this disease. However, genetic studies have so far yielded inconclusive and often conflicting results. This is probably a result of the complex etiology of this disorder, and the likelihood that there are multiple mechanisms by which an individual can attain the same, often clinically indistinguishable phenotype of osteoporosis. Thus, heterogeneous patient populations can undermine progress in identifying which and how genes influence the pathophysiologic processes associated with osteoporosis. In this proposal the challenge of studying a complex trait will be addressed in three ways. (1) A group of 100 severely affected men with idiopathic osteoporosis will be identified and characterized. (2) These individuals will be compared to an equal number of carefully matched, healthy male control subjects with specific reference to hormonal and physiologic indices, bone structural parameters and bone density. The range of phenotypes represented by these indicators and their relationship to osteoporosis will be described. Finally (3) approximately 400 family members of the index patients will be studied, with emphasis on recruiting large numbers of individuals from selected families, to test whether any physiologic and structural indicators cosegregate with osteoporosis in families and whether there is a gender- specificity to the transmission pattern of this disease. This grant will enable the applicant to develop an academic career in metabolic bone diseases with expertise in genetic analysis by allowing her (1) to continue to hone her research skills (2) to learn and apply methods of molecular, epidemiological and statistical genetics, and (3) to acquire independence as a clinical investigator.